# Transcriptomic signatures of menopause across human tissues

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $121,125

## Abstract

PROJECT SUMMARY
Unfortunately, women have increased coronary heart disease, stroke, and mortality risk after menopause. This
can be partially attributed to increases in cardiovascular disease (CVD) risk factors that many women experience
after menopause, such as blood pressure, lipid levels, and adiposity, but the mechanisms behind these and
other changes are poorly understood. A reduction in circulating estrogen levels is one of the major changes with
menopause, and estrogen can transcriptionally regulate many genes, often in a tissue-specific manner. Prior
studies of changes in gene expression with menopause have been limited, and most have been focused on
breast, bone, and female reproductive tissues. We hypothesize that transcriptomic examination of
cardiometabolic tissues across the menopause transition will reveal insight into the molecular processes
responsible for the increased CVD risk. Though menopause status information is missing from most human
tissue gene expression datasets, we hypothesize that menopausal status can be inferred from gene expression
data. To accomplish this, in Aim 1A we will infer the menopausal status of hundreds of female Genotype-Tisssue
Expression (GTEx) subjects based on the gene expression profiles of their female reproductive tissues, using a
combination of dimensionality reduction approaches informed by known biology and more agnostic, clustering-
based methodology. Since the average GTEx subject contributed samples from over 18 tissues, we will have
inferred menopausal status information for non-reproductive tissues as well. In a preliminary analysis of uterus
gene expression data (withholding age as a covariate), we observed clear classification of individuals into an
inferred premenopausal and an inferred postmenopausal group. In Aim 1B, we will use the inferred menopausal
status information from Aim 1A to identify genes and pathways that are differentially expressed in tissues derived
from inferred premenopausal versus postmenopausal women, focusing on cardiometabolic tissues of relevance
to cardiovascular disease, such as liver, adipose, and blood vessels. Finally, since menopause status is
confounded by age, in Aim 2 we will identify sex-specific aging genes in cardiometabolic GTEx tissues and other
existing human tissue gene expression datasets with age and sex information from suitable numbers of younger
(age<50) and older (age >50) adults and examine the relationship of gene expression with chronological age in
each sex subset. Inferred menopause-related genes that do not exhibit similar correlations with chronological
age in male tissues are likely to be regulated by the female-specific hormonal changes during menopause rather
than more general aging processes. Overall, this will be the most comprehensive evaluation of the effects of
menopause on gene expression performed to date, and the findings could identify molecular pathways
underlying the increased disease burden in post-menopausal women.

## Key facts

- **NIH application ID:** 10805413
- **Project number:** 5R21HL167188-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Elizabeth Theusch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $121,125
- **Award type:** 5
- **Project period:** 2023-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805413

## Citation

> US National Institutes of Health, RePORTER application 10805413, Transcriptomic signatures of menopause across human tissues (5R21HL167188-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10805413. Licensed CC0.

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